Methods of treating eye diseases associated with inflammation and vascular proliferation

ABSTRACT

Methods for treating eye diseases associated with inflammation and/or vascular proliferation in subjects are disclosed. The methods include administering therapeutically effective amounts of a tranilast compound, in particular (E)-2-[[3-(3-Methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or (E)-2-[[3,4-Bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or pharmaceutically acceptable salts or solvates thereof.

FIELD OF THE INVENTION

The present invention relates broadly to methods of treating eyediseases associated with inflammation and/or vascular proliferationincluding diabetic retinopathy. More particularly, the invention relatesto a method of treating these eye diseases with analogues of theanti-fibrotic agent, Tranilast, as well as a kit for treating these eyediseases.

BACKGROUND OF THE INVENTION

Ocular diseases that involve inflammation and/or vascular proliferationas a causal element(s) usually, but not always, relate to the anterior-and posterior-segments of the eye. For example, ocular disorders thathave an etiology in inflammation and/or vascular proliferation could becorneal edema, anterior and posterior uveitis, pterygium, cornealdiseases that are caused by infections from microbes or microorganismssuch as bacteria, viruses, fungi, amoebas and parasites, dry eye,conjunctivitis, allergy- and laser-induced exudation, non-age relatedmacular degeneration, macular edema, diabetic retinopathy (DR),age-related macular degeneration (Kim et al. 2001; A. M. Joussen et al.2004; S. C. Pflugfelder 2004) and ocular von Hippel-Lindau disease whichis characterised by fine vascular proliferation in the retina.

One of the ocular diseases mentioned above, DR, is a common complicationof diabetes and remains one of the leading causes of vision loss(Cheung, Fung et al. 2005; Santos, Tschiedel et al. 2005). Vision lossin DR develops by slow and progressive alterations to the retinalmicrovasculature (pericytes and endothelial cells) leading to breakdownof the blood-retinal barrier, pathological angiogenesis and scarring.Based on the extent of vascular abnormalities, DR can be broadlycategorized into non-proliferative DR (NPDR) and proliferative DR (PDR)(Klein, Klein et al. 2004). In NPDR, hyperglycaemia induces thickeningof capillary basement membrane, apoptosis or ‘dropout’ of pericytes,microaneurysms and vascular leakage. Blockade of retinal capillariescauses localized hypoxia, which increases the production of angiogenicgrowth factors. In some microvessels, endothelial cells become apoptoticresulting in acellular capillaries (devoid of both pericytes andendothelial cells), capillary closure and areas of retinalnon-perfusion. Adherent leukocytes may also contribute to the lesion bycausing retinal capillary occlusion (Joussen, Poulaki et al. 2004).Multiple haemorrhages, soft exudates, cotton wool spots, intraretinalmicrovascular abnormalities and venous beading and loops develop.Increased areas of tissue non-perfusion stimulate the production ofangiogenic factors leading to the proliferation of vessels, which is thehallmark feature of PDR. Retinal angiogenesis can be accompanied byfibrosis resulting in a fibrovascular ridge, which extends into thevitreous cavity or on the surface of the retina. Contraction of thefibrovascular ridge causes retinal detachment and vision loss andblindness (Watkins 2003).

The pathogenesis of DR is not fully understood. However, metabolic andbiochemical changes, such as increased flux of glucose through thepolyol pathway, activation of protein kinase C, oxidative damage andincreased advanced glycation endproduct formations are contributors inthe development of DR (Cheung, Fung et al. 2005). Accumulating evidencesindicate that vascular endothelial growth factor (VEGF) plays a criticalrole in angiogenesis (Sarlos, Rizkalla et al. 2003) in DR, whileintercellular adhesion molecule (ICAM-1) mediated leukocytosis resultingin secondary endothelial damage (Joussen, Poulaki et al. 2002;Khalfaoui, Lizard et al. 2009). Recently, DR has also been recognized asa chronic inflammatory disease (Adamis 2002; Joussen, Poulaki et al.2004). With this notion, studies demonstrated that anti-inflammatorytherapy prevents classic histopathological features of DR: acellularcapillary formation, retinal haemorrhage development, microaneurysmprogress, and pericyte loss (Adamis 2002; Joussen, Poulaki et al. 2002).

The current treatment for DR is laser photocoagulation, a procedure thatdestroys angiogenic vessels and the surrounding hypoxic tissue (Aiello2003).

Although beneficial, laser photocoagulation can destroy healthy retina,and the disease continues despite intensive treatment. Therefore, lessinvasive therapies are being investigated, with a particular focus onthe inhibition of injurious molecules such as VEGF and ICAM-1 (Arita,Hata et al.; Sarlos, Rizkalla et al. 2003; Khalfaoui, Lizard et al.2009). Nevertheless, there remains a need for further therapies fortreating eye diseases associated with inflammation and/or vascularproliferation such as diabetic retinopathy as well as corneal edema,anterior and posterior uveitis, pterygium, corneal diseases that arecaused by infections from microbes or microorganisms such as bacteria,viruses, fungi, amoebas and parasites, dry eye, conjunctivitis, allergy-and laser-induced exudation, non-age related macular degeneration,macular edema, age-related macular degeneration and ocular vonHippel-Lindau disease.

The reference to any prior art in this specification is not, and shouldnot be taken as an acknowledgement or any form of suggestion that thereferenced prior art forms part of the common general knowledge inAustralia.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a method for treatingan eye disease associated with inflammation and/or vascularproliferation in a subject including administering to the subject atherapeutically effective amount of a tranilast compound, or apharmaceutically acceptable salt or solvate thereof.

As used herein, the term “tranilast compound” refers to tranilast per seor a compound that one of ordinary skill in the art would understand asa derivative or analogue thereof such as the compounds of formulae 1 to20 described below. However, the term is not intended to limit thepresent invention to tranilast per se or compounds of formulae 1 to 20as other derivatives or analogues may also be suitable for use in thepresent invention.

However, as with any group of structurally related compounds whichpossess a particular utility, certain tranilast compounds may beparticularly useful in the present invention.

In some embodiments of the first aspect of the invention, the tranilastcompound is a compound of Formula 1

wherein R₁ and R₂, which may be the same or different, are selected fromthe group consisting of H, NHR₆, NR₆R₇, OR₈, halogen, C₁ to C₁₀ alkyl,C₃ to C₁₀ cycloalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C₁₀ alkene, C₃to C₁₀ alkyne, aryl, C₅ to C₂₀ alkaryl, fused C₅ to C₂₀ aryl or alkaryl,and a hydrocarbon chain containing a heterocyclic or fused ring, any ofwhich may be optionally substituted;

R₃ is selected from the group consisting of H, C₁ to C₁₀ alkyl, C₃ toC₁₀ cycloalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to C₁₀alkyne, aryl, C₅ to C₂₀ alkaryl, and a hydrocarbon chain containing aheterocyclic or fused ring, any of which may be optionally substituted;

R₄ is selected from the group consisting of H, OH, OR₆, NHR₆ and NR₆R₇;

R₅ is selected from the group consisting of H, NHR₆, NR₆R₇, OR₈,halogen, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, C₃ to C₁₀cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to C₁₀ alkyne, aryl, C₅ to C₂₀alkaryl, fused C₅ to C₂₀ aryl or alkaryl, and a hydrocarbon chaincontaining a heterocyclic or fused ring, any of which may be optionallysubstituted;

X₁ and X₂, which may be the same or different, are selected from thegroup consisting of a bond, C, O, N and S;

X₃ is C or N;

T is a single or double bond;

m is the integer 0 or 1;

n is an integer between 0 and 4;

R₆ and R₇, which may be the same or different, are selected from thegroup consisting of H, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, C₃ to C₁₀cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to C₁₀ alkyne, aryl, C₅ to C₂₀alkaryl, and a hydrocarbon chain containing a heterocyclic or fusedring, any of which may be optionally substituted;

R₈ is selected from the group consisting of H, C₁ to C₁₀ alkyl, C₃ toC₁₀ cycloalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to C₁₀alkyne, aryl, C₅ to C₂₀ alkaryl, and a hydrocarbon chain containing aheterocyclic or fused ring, any of which may be optionally substituted;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, or metabolites thereof.

In some embodiments of the first aspect of the invention, the tranilastcompound is a compound of Formula 2

wherein R₁ and R₂, which may be the same or different, are selected fromthe group consisting of a C₁ to C₁₀ alkyl, C₃ to C_(o1) cycloalkyl, C₃to C₁₀ cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to C₁₀ alkyne and a chaincontaining a heterocyclic or fused ring, any of which may be optionallysubstituted;

X₁ and X₂ are the same or different and are selected from the groupconsisting of a bond, O, N and S;

T is a single or double bond;

R₃ is selected from the group consisting of H, C₃ to C₁₀ alkene, C₃ toC₁₀ alkyne and a chain containing a heterocyclic or fused ring, any ofwhich may be optionally substituted;

R₄ is selected from the group consisting of H, OH, OR₆, NHR₆ and NR₆R₇;

R₅ is selected from the group consisting of H, NHR₆, NR₆R₇, OR₈,halogen, C₃ to C₁₀ alkene, C₃ to C₁₀ alkyne and a chain consisting of aheterocyclic or fused ring, any of which may be optionally substituted;

R₆ and R₇, which may be the same or different, are selected from thegroup consisting of H, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, C₃ to C₁₀cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to C₁₀ alkyne, aryl, C₅ to C₂₀alkaryl, and a hydrocarbon chain containing, a heterocyclic or fusedring, any of which may be optionally substituted;

R₈ is selected from the group consisting of H, C₁ to C₁₀ alkyl, C₃ toC₁₀ cycloalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to C₁₀alkyne, aryl, C₅ to C₂₀ alkaryl, and a hydrocarbon chain containing aheterocyclic or fused ring, any of which may be optionally substituted;and

n is an integer between 0 and 4;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof and metabolites thereof.

In another embodiment of the first aspect of the invention, thetranilast compound is a compound of Formula 3

wherein R₉ or R₁₀, which may be the same or different, are selected fromthe group consisting of H, C₁ to C₁₀ alkyl, C₃ to C₈ terminal ornon-terminal alkyne or a cyclopentyl, cyclohexyl, cyclohexylmethyl orcyclopentylmethyl group;

R₅ and n are as described above in respect of formulae 1 and 2;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

In some embodiments of the first aspect of the invention, the tranilastcompound is a compound of Formula 4 or Formula 5

where p is an integer between 1 and 10; and R is selected from the groupconsisting of H and C₁ to C₁₀ alkyl;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

In yet another embodiment of the first aspect of the invention, thetranilast compound is a compound of Formula 6 or Formula 7

wherein G is a cyclopentyl ring, a cyclohexyl ring or a1,4-disubstituted 1,2,3-triazole ring; and

q is an integer between 0 and 6;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

Non-limiting examples of suitable tranilast compounds of formulae 1 to 7as described above include:

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

In a preferred embodiment of the first aspect of the present invention,the tranilast compound has the formula

or a pharmaceutically acceptable salt thereof.

In alternate embodiments of the first aspect of the invention, thetranilast compound has the formula 8

wherein:

T is a single bond, a double bond or a triple bond;

R¹, R², R³, R⁴, and R⁵ are each independently selected from the groupconsisting of: H, halogen, OH, NO₂, CN, NH₂, optionally substitutedC₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionallysubstituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl,optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₂-C₁₂ heterocycloalkyl, optionallysubstituted C₂-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionally substituted C₁-C₁₈ heteroaryl, optionally substitutedC₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionallysubstituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionallysubstituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂heterocycloalkyloxy, optionally substituted C₁-C₁₂heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionallysubstituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂alkylamino, SR¹¹, SO₃H, SO₂NR¹¹R¹², SO₂R¹¹, SONR¹¹R¹², SOR¹¹, COR¹¹,COOH, COOR¹¹, CONR¹¹R¹², NR¹¹COR¹², NR¹¹COOR¹², NR¹¹SO₂R¹²,NR¹¹CONR¹²R¹³, NR¹¹R¹², and acyl; provided that at least one of R¹, R²,R³, R⁴, and R⁵ contains a halogen;

R⁶ and R⁷ are present when T is a single bond or a double bond but notwhen T is a triple bond, each R⁶ and R⁷ being independently selectedfrom the group consisting of: H, NO₂, CN, optionally substituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substitutedC₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionallysubstituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₂-C₁₂ heterocycloalkyl, optionallysubstituted C₂-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionally substituted C₁-C₁₈ heteroaryl, optionally substitutedC₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionallysubstituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionallysubstituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂heterocycloalkyloxy, optionally substituted C₁-C₁₂heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionallysubstituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂alkylamino, SR¹¹, SO₃H, SO₂NR¹¹R¹², SO₂R¹¹, SONR¹¹R¹², SOR¹¹, COR¹¹,COOH, COOR¹¹, CONR¹¹R¹², NR¹¹COR¹², NR¹¹COR¹², NR¹¹SO₂R¹²,NR¹¹CONR¹²R¹³, NR¹¹R¹², and acyl;

R⁸ is selected from the group consisting of: H, a N-protecting group,optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substitutedC₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionallysubstituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈ aryl, and optionally substituted C₁-C₁₈heteroaryl;

R⁹ is selected from the group consisting of: H, COOR¹¹, CONR¹¹R¹²,COSR¹¹, OR¹¹, NR¹¹R¹², and SR¹¹;

R¹⁰ is selected from the group consisting of: H, halogen, OH, NO₂, CN,NH₂, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substitutedC₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionallysubstituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionallysubstituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy,optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substitutedC₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy,optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionallysubstituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionallysubstituted C₁-C₁₂ alkylamino, SR¹¹, SO₃H, SO₂NR¹¹R¹², SO₂R¹¹,SONR¹¹R¹², SOR¹¹, COR¹¹, COOH, COOR¹¹, CONR¹¹R¹², NR¹¹COR¹², NR¹¹COOR¹²,NR¹¹SO₂R¹², NR¹¹CONR¹²R¹³, NR¹¹R¹², and acyl;

each R¹¹, R¹² and R¹³ is independently selected from the groupconsisting of H, optionally substituted C₁-C₁₂ alkyl, optionallysubstituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl,optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionallysubstituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂heterocycloalkenyl, optionally substituted C₆-C₁₈ aryl, and optionallysubstituted C₁-C₁₈ heteroaryl;

m is an integer selected from the group consisting of 0, 1, 2, 3, and 4;

n is an integer selected from the group consisting of 1, 2, 3, and 4,and 5; and

m+n is an integer selected from the group consisting of 1, 2, 3, 4, and5;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

In a preferred embodiment of the first aspect of the invention, thetranilast compound of formula 8 described immediately above has theformula 9

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

In another preferred embodiment of the first aspect of the invention,the tranilast compound of formula 8 described above has the formula 10

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

Non-limiting examples of suitable tranilast compounds of formulae 8 to10 as described above include:

or a pharmaceutically acceptable salt thereof.

In a preferred embodiment of the first aspect of the present invention,the tranilast compound has the formula

or a pharmaceutically acceptable salt thereof.

In some embodiments of the first aspect of the invention, the tranilastcompound has the formula 11

wherein;

X¹(YZ) is C═O, C(F₂) or SO₂;

X² is NR¹⁰ or (CH₂)_(p);

T is a double bond, a triple bond or when T is a single bond, one pairof R⁶ and R⁷ are fused to form a cyclopropane ring of the formula

A is selected from the group consisting of C₃ to C₁₂ cycloalkyl, C₃ toC₁₂ cycloalkenyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂heterocycloalkenyl, C₆-C₁₈ aryl and C₆ to C₁₈ heteroaryl;

R¹, R⁴ and R⁵ are each independently selected from the group consistingof: H, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionallysubstituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl,optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionallysubstituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy,optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionallysubstituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂heterocycloalkyloxy, optionally substituted C₁-C₁₂heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionallysubstituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³,COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴,NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴, and acyl;

R² and R³, are each independently selected from the group consisting of:H, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionallysubstituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl,optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionallysubstituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy,optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionallysubstituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂heterocycloalkyloxy, optionally substituted C₁-C₁₂heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionallysubstituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³,COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴,NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴ and acyl; or

R² and R³ may be fused to form a 5 or 6 membered cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring each of which may beoptionally substituted;

one pair of R⁶ and R⁷ are present when T is a double bond but R⁶ and R⁷are not present when T is a triple bond, each R⁶ and R⁷ beingindependently selected from the group consisting of: H, NO₂, CN,optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substitutedC₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionallysubstituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionallysubstituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy,optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substitutedC₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy,optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionallysubstituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionallysubstituted C₁-C₁₂ alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³,SONR¹³R¹⁴, SOR¹³, COR¹⁴, COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴,NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴, and acyl;

R⁸ is selected from the group consisting of H, halogen, OH, NO₂, CN,NH₂, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substitutedC₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionallysubstituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ alkyloxy,optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionallysubstituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy,optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionallysubstituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy,optionally substituted C₁-C₁₂ alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴,SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³, COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴,NR¹³COOR¹⁴, NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵ and NR¹³R¹⁴ and acyl;

R⁹ is selected from the group consisting of OH, OR¹³, COOR¹³, CONR¹³R¹⁴,NR¹³R¹⁴, tetrazol-5-yl, SO₂R¹³, SO₂NR¹³R¹⁴ and CONHOR¹³;

R¹⁰ is selected from the group consisting of H, a N-protecting group,optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substitutedC₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionallysubstituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈aryl, and optionally substitutedC₁-C₁₈heteroaryl;

R¹¹ and R¹² are independently selected from the group consisting of H,halogen, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl,optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionallysubstituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₂-C₁₂ heterocycloalkyl, optionallysubstituted C₂-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionally substituted C₁-C₁₈ heteroaryl, optionally substitutedC₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionallysubstituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionallysubstituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂heterocycloalkyloxy, optionally substituted C₁-C₁₂heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionallysubstituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³,COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴,NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴, and acyl;

each R¹³, R¹⁴, R¹⁵ are each independently selected from the groupconsisting of H, —OH, optionally substituted C₁-C₁₂ alkyl, optionallysubstituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl,optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl; optionallysubstituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, and optionallysubstituted C₁-C₁₈heteroaryl;

n is an integer selected from the group consisting of 0, 1, 2, 3, and 4;

m is an integer selected from the group consisting of 1, 2, 3, and 4;

m+n is an integer selected from the group consisting of 1, 2, 3, 4, and5; and

p is an integer selected from the group consisting of 0, 1, 2, 3, 4, and5;

and when X¹(YZ) is C(F₂) or SO₂; or

when T is a cyclopropane ring as defined above; or

when R¹ and R⁵ are H and T is a double bond; or

when X² is (CH₂)_(p) and p is 0 or 1; or

when A is selected from the group consisting of C₃ to C₁₂ cycloalkyl,preferably C₄ to C₆ cycloalkyl, C₁ to C₁₂ heterocycloalkenyl, and C₆ toC₁₈ heteroaryl;

then R² and R³ may also be independently selected from —X³—R¹⁶ or—X⁴—R¹⁷;

wherein X³ and X⁴ may be the same or different and are selected from thegroup consisting of a bond C, O, N and S; and

R¹⁶ and R¹⁷ may be the same or different and are selected from the groupconsisting of H, NHR¹³, NR¹³R¹⁴, OR¹³, halogen, C₁ to C₁₀ alkyl, C₃ toC₁₀ cycloalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to C₁₀alkyne, aryl, C₅ to C₂₀ alkaryl, fused C₅ to C₂₀ aryl or alkaryl and ahydrocarbon chain containing a heterocyclic or fused ring, any of whichmay be optionally substituted;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

In a preferred embodiment of the first aspect of the invention, thetranilast compound of formula 11 described above has the formula 12

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

In another preferred embodiment of the first aspect of the invention,the tranilast compound of formula 11 described above has the formula 13

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

In yet another preferred embodiment of the first aspect of theinvention, the tranilast compound of formula 11 described above has theformula 14

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

In another embodiment of the first aspect of the invention, thetranilast compound of formula 11 described above has the formula 15

wherein Het represents a heterocyclic ring;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

In some embodiments of the first aspect of the invention, the tranilastcompound of formula 11 described above has the formula 16

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

Non-limiting examples of suitable tranilast compounds of formulae 11 and12 as described above include:

or a pharmaceutically acceptable salt thereof.

Non-limiting examples of suitable tranilast compounds of formulae 11 and13 as described above include:

or a pharmaceutically acceptable salt thereof.

Non-limiting examples of suitable tranilast compounds of formulae 11 and14 as described above include:

or a pharmaceutically acceptable salt thereof.

More non-limiting examples of suitable tranilast compounds of formulae11 include:

or a pharmaceutically acceptable salt thereof.

Non-limiting examples of suitable tranilast compounds of formulae 11 and16 as described above include:

wherein p is 0 or 1;

or a pharmaceutically acceptable salt thereof.

In some embodiments of the first aspect of the invention, the tranilastcompound has the formula 17

wherein:

W is selected from the group consisting of: CR⁷ and N;

A is selected from the group consisting of:—(CR⁸R⁹)_(p)—(Y)_(q)—(C(O))_(r)—(CR¹⁰R¹¹)_(s)— and—(CR⁸R⁹)_(p)—(C(O))_(r)—(Y)_(q)—(CR¹⁰R¹¹)_(s)—, wherein Y is selectedfrom the group consisting of: O, S, NR¹², each p and s are an integerindependently selected from the group consisting of 0, 1, and 2, each qand r are an integer independently selected from the group consisting of0 and 1, and p+q+r+s is an integer selected from the group consisting of1, 2, and 3;

Z¹-Z² is selected from the group consisting of N—C═ and C═C;

X¹ selected from the group consisting of: C═O, CF₂ or SO₂, PO₂;

X² is selected from the group consisting of: NR¹³ and (CH₂)_(t) whereint is an integer selected from the group consisting of: 0 and 1;

D is selected from the group consisting of: a cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroarylring;

R¹, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selectedfrom the group consisting of: H, halogen, OH, NO₂, CN, NH₂, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionallysubstituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionallysubstituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy,optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substitutedC₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy,optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionallysubstituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionallysubstituted C₁-C₁₂ alkylamino, SR¹⁴, SO₃H, SO₂NR¹⁵R¹⁶, SO₂R¹⁴,SONR¹⁵R¹⁶, SOR¹⁴, COR¹⁴, COOH, COOR¹⁴, CONR¹⁵R¹⁶, NR¹⁵COR¹⁴, NR¹⁵COOR¹⁴,NR¹⁵SO₂R¹⁴, NR¹⁵CONR¹⁵R¹⁶, NR¹⁵R¹⁶, and acyl;

R² and R³, are each independently selected from the group consisting of:H, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionallysubstituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl,optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionallysubstituted C₂-C₁₂ heterocycloalkyl, optionally substituted C₂-C₁₂heterocycloalkenyl, optionally substituted C₆-C₁₈ aryl, optionallysubstituted C₁-C₁₈ heteroaryl, optionally substituted C₁-C₁₂ alkyloxy,optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionallysubstituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy,optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionallysubstituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy,optionally substituted C₁-C₁₂ alkylamino, SR¹⁴, SO₃H, SO₂NR¹⁵R¹⁶,SO₂R¹⁴, SONR¹⁵R¹⁶, SOR¹⁴, COR¹⁴, COOH, COOR¹⁴, CONR¹⁵R¹⁶, NR¹⁵COR¹⁴,NR¹⁵COOR¹⁴, NR¹⁵SO₂R¹⁴, NR¹⁵CONR¹⁶R¹⁷, NR¹⁵R¹⁶, and acyl; or R² and R³may be fused to form a 5 or 6 membered cycloalkyl, heterocycloalkyl,aryl or heteroaryl ring each of which may be optionally substituted;

R¹², R¹³, R¹⁵, R¹⁶, and R¹⁷ are each independently selected from thegroup consisting of: H, an N-protecting group, optionally substitutedC₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionallysubstituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl,optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionallysubstituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈ heteroaryl;

R¹⁴ is selected from the group consisting of H, optionally substitutedC₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionallysubstituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl,optionally substituted C₃-C₁₂ cycloalkyl, optionally substitutedC₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl,optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substitutedC₆-C₁₈ aryl, and optionally substituted C₁-C₁₈ heteroaryl;

m is an integer selected from the group consisting of 0, 1, 2, 3, and 4;

n is an integer selected from the group consisting of 1, 2, 3, 4, and 5;

m+n is an integer selected from the group consisting of 1, 2, 3, 4, and5;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

Non-limiting examples of suitable tranilast compounds of formula 17 asdescribed above include:

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment of the first aspect of the invention, thetranilast compound has the formula 18

A is selected from the group consisting of:—(CR⁸R⁹)_(p)—(Y)_(q)—(C(O))_(r)—(CR¹⁰R¹¹)_(s)— and—(CR⁸R⁹)_(p)—(C(O))_(r)—(Y)_(q)—(CR¹⁰R¹¹)_(s)—, wherein Y is selectedfrom the group consisting of: O, S, and NR¹², each p and s are aninteger independently selected from the group consisting of: 0, 1, and2, each q and r are an integer independently selected from the groupconsisting of: 0 and 1, and p+q+r+s is an integer selected from thegroup consisting of: 1, 2, and 3;

X¹ is selected from the group consisting of: C═O, CF₂, and SO₂, PO₂;

X² is selected from the group consisting of: NR¹³ or (CH₂)_(t) wherein tis an integer selected from the group consisting of: 0 and 1;

D is selected from the group consisting of: a cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroarylring;

R¹, R² and R³, are each independently selected from the group consistingof: H, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionallysubstituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl,optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionallysubstituted C₂-C₁₂ heterocycloalkyl, optionally substituted C₂-C₁₂heterocycloalkenyl, optionally substituted C₆-C₁₈ aryl, optionallysubstituted C₁-C₁₈ heteroaryl, optionally substituted C₁-C₁₂ alkyloxy,optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionallysubstituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy,optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionallysubstituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy,optionally substituted C₁-C₁₂ alkylamino, SR¹⁴, SO₃H, SO₂NR¹⁵R¹⁶,SO₂R¹⁴, SONR¹⁵R¹⁶, SOR¹⁴, COR¹⁴, COOH, COOR¹⁴, CONR¹⁵R¹⁶, NR¹⁵COR¹⁴,NR¹⁵COOR¹⁴, NR¹⁵SO₂R¹⁴, NR¹⁵CONR¹⁶R¹⁷, NR¹⁵R¹⁶, and acyl; or R² and R³may be fused to form a 5 or 6 membered cycloalkyl; heterocycloalkyl,aryl or heteroaryl ring each of which may be optionally substituted;

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected fromthe group consisting of: H, halogen, OH, NO₂, CN, NH₂, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionallysubstituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionallysubstituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy,optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substitutedC₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy,optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionallysubstituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionallysubstituted C₁-C₁₂ alkylamino, SR¹⁴, SO₃H, SO₂NR¹⁵R¹⁶, SO₂R¹⁴,SONR¹⁵R¹⁶, SOR¹⁴, COR¹⁴, COOH, COOR¹⁴, CONR¹⁵R¹⁶, NR¹⁵COR¹⁴, NR¹⁵COOR¹⁴,NR¹⁵SO₂R¹⁴, NR¹⁵CONR¹⁶R¹⁷, NR¹⁵R¹⁶, and acyl;

R¹², R¹³, R¹⁵, R¹⁶, and R¹⁷ are each independently selected from thegroup consisting of: H, a N-protecting group, optionally substitutedC₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionallysubstituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl,optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionallysubstituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈ heteroaryl;

R¹⁴ is selected from the group consisting of H, optionally substitutedC₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionallysubstituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl,optionally substituted C₃-C₁₂ cycloalkyl, optionally substitutedC₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl,optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substitutedC₆-C₁₈ aryl, and optionally substituted C₁-C₁₈ heteroaryl;

m is an integer selected from the group consisting of: 0, 1, 2, 3, and4;

n is an integer selected from the group consisting of: 1, 2, 3, 4, and5;

m+n is an integer selected from the group consisting of: 1, 2, 3, 4, and5;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

Non-limiting examples of suitable tranilast compounds of formula 18 asdescribed above include:

or a pharmaceutically acceptable salt or prodrug thereof.

In yet another embodiment of the first aspect of the invention, thetranilast compound has the formula 19

A is selected from the group consisting of:—(CR⁹R¹⁰)_(p)—(Y)_(q)—(C(O))_(r)—(CR¹¹R¹²)_(s)— and—(CR⁹R¹⁰)_(p)—(C(O))_(r)—(Y)_(q)—(CR¹¹R¹²)_(s)—, wherein Y is selectedfrom the group consisting of: O, S, NR¹³, each p and s are an integerindependently selected from the group consisting of: 0, 1, and 2, each qand r are an integer independently selected from the group consistingof: 0 and 1, and p+q+r+s is an integer selected from the groupconsisting of: 1, 2, and 3;

T is selected from the group consisting of: a single bond, a doublebond, a triple bond and

X¹ is selected from the group consisting of: C═O, CF₂ or SO₂, PO₂;

X² is selected from the group consisting of: CR¹⁷ and N;

Z¹, Z², Z³, and Z⁴ are each independently selected from the groupconsisting of CR⁸ and N;

R¹, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁵ and R¹⁶ are each independentlyselected from the group consisting of: H, halogen, OH, NO₂, CN, NH₂,optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substitutedC₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionallysubstituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈ aryl, optionally substituted C₁₋C₁₈heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionallysubstituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy,optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substitutedC₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy,optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionallysubstituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionallysubstituted C₁-C₁₂ alkylamino, SR¹⁸, SO₃H, SO₂NR¹⁹R²⁰, SO₂R¹⁸,SONR¹⁹R²⁰, SOR¹⁸, COR¹⁸, COOH, COOR⁸, CONR¹⁹R²⁰, NR¹⁹COR¹⁸, NR¹⁹COOR¹⁸,NR¹⁹SO₂R¹⁸, NR¹⁹CONR²⁰R²¹, NR¹⁹R²⁰, and acyl;

R² and R³, are each independently selected from the group consisting of:H, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionallysubstituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl,optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionallysubstituted C₂-C₁₂ heterocycloalkyl, optionally substituted C₂-C₁₂heterocycloalkenyl, optionally substituted C₆-C₁₈ aryl, optionallysubstituted C₁-C₁₈ heteroaryl, optionally substituted C₁-C₁₂ alkyloxy,optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionallysubstituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy,optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionallysubstituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy,optionally substituted C₁-C₁₂ alkylamino, SR¹⁸, SO₃H, SO₂NR¹⁹R²⁰,SO₂R¹⁸, SONR¹⁹R²⁰, SOR¹⁸, COR¹⁸, COOH, COOR¹⁸, CONR¹⁹R²⁰, NR¹⁹COR¹⁸,NR¹⁹COOR¹⁸, NR¹⁹SO₂R¹⁸, NR¹⁹CONR²⁰R²¹, NR¹⁹R²⁰, and acyl; or R² and R³may be fused to form a 5 or 6 membered cycloalkyl, heterocycloalkyl,aryl or heteroaryl ring, each of which may be optionally substituted;

R⁶ and R⁷ are present when T is a single bond, a double bond or

but not when T is a triple bond, each R⁶ and R⁷ being independentlyselected from the group consisting of: H, NO₂, CN, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionallysubstituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionallysubstituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy,optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substitutedC₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy,optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionallysubstituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionallysubstituted C₁-C₁₂ alkylamino, SR¹⁸, SO₃H, SO₂NR¹⁹R²⁰, SO₂R¹⁸,SONR¹⁹R²⁰, SOR¹⁸, COR¹⁸, COOH, COOR¹⁸, CONR¹⁹R²⁰, NR¹⁹COR¹⁸, NR¹⁹COOR¹⁸,NR¹⁹SO₂R¹⁸, NR¹⁹CONR²⁰R²¹, NR¹⁹R²⁰, and acyl;

R¹³, R¹⁹, R²⁰ and R²¹ are each independently selected from the groupconsisting of: H: a N-protecting group, optionally substituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substitutedC₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionallysubstituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionallysubstituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈ heteroaryl;

R¹⁸ is selected from the group consisting of H, optionally substitutedC₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionallysubstituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl,optionally substituted C₃-C₁₂ cycloalkyl, optionally substitutedC₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl,optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substitutedC₆-C₁₈ aryl, and optionally substituted C₁-C₁₈ heteroaryl;

n is an integer selected from the group consisting of: 0, 1, 2, 3, and4;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

Non-limiting examples of suitable tranilast compounds of formula 19 asdescribed above include:

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment of the first aspect of the invention, thetranilast compound has the formula 20

wherein:

Z—X—Y is selected from the group consisting of: N═C—N, N—C═N, O—C═N,S—C═N, N═C—O, N═C—S, C═C—NH, C═C—O, C═C—S, and C(O)—C═N;

A is selected from the group consisting of: a bond, SO₂, C, C═S, C═O,C═NR⁹, and NR⁹;

T is selected from the group consisting of: a single bond, a doublebond, a triple bond, and

Z¹, Z², Z³, and Z⁴ are each independently selected from the groupconsisting of CR⁸ and N;

R¹, R⁴, R⁵, R⁸, R¹⁰, and R¹¹ are each independently selected from thegroup consisting of: H, halogen, OH, NO₂, CN, NH₂, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionallysubstituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionallysubstituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy,optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substitutedC₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy,optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionallysubstituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionallysubstituted C₁-C₁₂ alkylamino, SR¹², SO₃H, SO₂NR¹³R¹⁴, SO₂R¹²,SONR¹³R¹⁴, SOR¹², COR¹², COOH, COOR¹², CONR¹³R¹⁴, NR¹³COR¹², NR¹³COOR¹²,NR¹³SO₂R¹², NR¹³CONR¹⁴R¹⁵, NR¹⁴R¹⁵, and acyl;

R² and R³, are each independently selected from the group consisting of:H, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionallysubstituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl,optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionallysubstituted C₂-C₁₂ heterocycloalkyl, optionally substituted C₂-C₁₂heterocycloalkenyl, optionally substituted C₆-C₁₈ aryl, optionallysubstituted C₁-C₁₈ heteroaryl, optionally substituted C₁-C₁₂ alkyloxy,optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionallysubstituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy,optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionallysubstituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy,optionally substituted C₁-C₁₂ alkylamino, SR¹², SO₃H, SO₂NR¹³R¹⁴,SO₂R¹², SONR¹³R¹⁴, SOR¹², COR¹², COOH, COOR¹², CONR¹³R¹⁴, NR¹³COR¹²,NR¹³COOR¹², NR¹³SO₂R¹², NR¹³CONR¹⁴R¹⁵, NR¹⁴R¹⁵, and acyl; or R² and R³may be fused to form a 5 or 6 membered cycloalkyl, heterocycloalkyl,aryl or heteroaryl ring each of which may be optionally substituted;

R⁶ and R⁷ are present when T is a single bond, a double bond or

but not when T is a triple bond, each R⁶ and R⁷ being independentlyselected from the group consisting of: H, NO₂, CN, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionallysubstituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionallysubstituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy,optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substitutedC₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy,optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionallysubstituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionallysubstituted C₁-C₁₂ alkylamino, SR¹², SO₃H, SO₂NR¹³R¹⁴, SO₂R¹²,SONR¹³R¹⁴, SOR¹², COR¹², COOH, COOR¹², CONR¹³R¹⁴, NR¹³COR¹², NR¹³COOR¹²,NR¹³SO₂R¹², NR¹³CONR¹⁴R¹⁵, NR¹⁴R¹⁵, and acyl;

R⁹, R¹³, R¹⁴, and R¹⁵ are each independently selected from the groupconsisting of: H, an N-protecting group, optionally substituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substitutedC₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionallysubstituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionallysubstituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈ heteroaryl;

R¹² is selected from the group consisting of H, optionally substitutedC₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionallysubstituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl,optionally substituted C₃-C₁₂ cycloalkyl, optionally substitutedC₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl,optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substitutedC₆-C₁₈ aryl, and optionally substituted C₁-C₁₈ heteroaryl;

n is an integer selected from the group consisting of: 0, 1, 2, 3, and4;

or derivatives thereof, analogues thereof, pharmaceutically acceptablesalts thereof, and metabolites thereof.

Non-limiting examples of suitable tranilast compounds of formula 20 asdescribed above include:

or a pharmaceutically acceptable salt or prodrug thereof.

One of ordinary skill in the art will appreciate that a variety oftranilast compounds may be used in the first aspect of the presentinvention.

The eye disease associated with inflammation and/or vascularproliferation in a subject is not intended to be particularly limited.In some embodiments of the first aspect of the invention, the eyedisease may be selected from the group comprising diabetic retinopathy,corneal edema, anterior and posterior uveitis, pterygium, cornealdiseases, dry eye, conjunctivitis, allergy- and laser-induced exudation,non-age related macular degeneration, macular edema, age-related maculardegeneration and ocular von Hippel-Lindau disease.

In a further embodiment of the first aspect of the invention, thecorneal disease is caused by infection from a microbe or microorganism.The microbe or microorganism may be selected from any of the groupscomprising bacteria, viruses, fungi, amoebas, and parasites.

Preferably, the eye disease is diabetic retinopathy in the first aspectof the invention.

As used herein, treating the eye disease includes inhibiting theprogression of the eye disease, preventing the eye disease, and/orameliorating a symptom of the eye disease.

In a second aspect, the present invention provides a use of at least onetranilast compound or a pharmaceutically acceptable salt or solvatethereof in the preparation of a pharmaceutical composition for treatingan eye disease associated with inflammation and/or vascularproliferation.

In preferred embodiments of the second aspect of the invention, thetranilast compound is a compound of any one of formulae 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 as describedabove in relation to the first aspect of the invention.

In another preferred embodiment of the second aspect of the invention,the tranilast compound may be a compound of the non-limiting examples ofsuitable tranilast compounds of formulae 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 described above in relation tothe first aspect of the invention.

In a particularly preferred embodiment of the second aspect of theinvention, the tranilast compound has the formula

or a pharmaceutically acceptable salt thereof.

In another particularly preferred embodiment of the second aspect of thepresent invention, the tranilast compound has the formula

or a pharmaceutically acceptable salt thereof.

In some embodiments of the second aspect of the invention, the eyedisease may be selected from the group comprising diabetic retinopathy,corneal edema, anterior and posterior uveitis, pterygium, cornealdiseases, dry eye, conjunctivitis, allergy- and laser-induced exudation,non-age related macular degeneration, macular edema, age-related maculardegeneration and ocular von Hippel-Lindau disease.

In a further embodiment of the second aspect of the invention, thecorneal disease is caused by infection from a microbe or microorganism.The microbe or microorganism may be selected from any of the groupscomprising bacteria, viruses, fungi, amoebas, and parasites.

Preferably, the eye disease is diabetic retinopathy in the second aspectof the invention.

In a third aspect, the present invention provides a use of at least onetranilast compound, or a pharmaceutically acceptable salt or solvatethereof, in the treatment of an eye disease associated with inflammationand/or vascular proliferation disease.

In a fourth aspect, the present invention provides a kit for treating aneye disease associated with inflammation and/or vascular proliferationincluding: at least one tranilast compound or a pharmaceuticallyacceptable salt or solvate thereof; and

instructions for administering the tranilast-type compound to a subjectin order to treat the eye disease.

In a fifth aspect, the present invention provides a tranilast compoundfor treating an eye disease associated with inflammation and/or vascularproliferation.

In preferred embodiments of the third, fourth or fifth aspects of theinvention, the tranilast compound is a compound of any one of formulae1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20as described above in relation to the first aspect of the invention.

In another preferred embodiment of the third, fourth or fifth aspects ofthe invention, the tranilast compound may be a compound of thenon-limiting examples of suitable tranilast compounds of formulae 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20described above in relation to the first aspect of the invention.

In a particularly preferred embodiment of the third, fourth or fifthaspects of the invention, the tranilast compound has the formula

or a pharmaceutically acceptable salt thereof.

In another particularly preferred embodiment of the third, fourth orfifth aspects of the invention, the tranilast compound has the formula

or a pharmaceutically acceptable salt thereof.

In some embodiments of the third, fourth or fifth aspects of theinvention, the eye disease may be selected from the group comprisingdiabetic retinopathy, corneal edema, anterior and posterior uveitis,pterygium, corneal diseases, dry eye, conjunctivitis, allergy- andlaser-induced exudation, macular degeneration, macular edema,age-related macular degeneration and ocular von Hippel-Lindau disease.

In a further embodiment of the third, fourth or fifth aspects of theinvention, the corneal disease is caused by infection from a microbe ormicroorganism. The microbe or microorganism may be selected from thegroup comprising bacteria, viruses, fungi, amoebas, and parasites.

Again, it is preferred the eye disease is diabetic retinopathy in thethird, fourth or fifth aspects of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In this specification a number of terms are used which are well known toa skilled addressee. Nevertheless for the purposes of clarity a numberof terms will be defined.

As used herein, the term “unsubstituted” means that there is nosubstituent or that the only substituents are hydrogen.

The term “optionally substituted” as used throughout the specificationdenotes that the group may or may not be further substituted or fused(so as to form a condensed polycyclic system), with one or morenon-hydrogen substituent groups. In certain embodiments the substituentgroups are one or more groups independently selected from the groupconsisting of halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃, alkyl, alkenyl,alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl,cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl,heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl, alkoxyaryl,alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy,alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy,arylalkyloxy, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino,aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl,alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl,arylsulfinyl, aminosulfinylaminoalkyl, —COOH, —COR¹¹, —C(O)OR¹¹,CONHR¹¹, NHCOR¹¹, NHCOOR¹¹, NHCONHR¹¹, C(═NOH)R¹¹, —SH, —SR¹¹, —OR¹¹ andacyl, wherein R¹¹ is H, optionally substituted C₁-C₁₂alkyl, optionallysubstituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂ alkynyl,optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionallysubstituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂heterocycloalkenyl, optionally substituted C₆-C₁₈ aryl, optionallysubstituted C₁-C₁₈ heteroaryl, and acyl.

“Alkyl” as a group or part of a group refers to a straight or branchedaliphatic hydrocarbon group, preferably a C₁-C₁₄ alkyl, more preferablyC₁-C₁₀ alkyl, most preferably C₁-C₆ unless otherwise noted. Examples ofsuitable straight and branched C₁-C₆ alkyl substituents include methyl,ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and thelike. The group may be a terminal group or a bridging group.

“Alkylamino” includes both mono-alkylamino and dialkylamino, unlessspecified. “Mono-alkylamino” means a —NH-Alkyl group, in which alkyl isas defined above. “Dialkylamino” means a —N(alkyl)₂ group, in which eachalkyl may be the same or different and are each as defined herein foralkyl. The alkyl group is preferably a C₁-C₆ alkyl group. The group maybe a terminal group or a bridging group.

“Arylamino” includes both mono-arylamino and di-arylamino unlessspecified. Mono-arylamino means a group of formula arylNH—, in whicharyl is as defined herein. di-arylamino means a group of formula(aryl)₂N— where each aryl may be the same or different and are each asdefined herein for aryl. The group may be a terminal group or a bridginggroup.

“Acyl” means an alkyl-CO— group in which the alkyl group is as describedherein. Examples of acyl include acetyl and benzoyl. The alkyl group ispreferably a C₁-C₆ alkyl group. The group may be a terminal group or abridging group.

“Alkenyl” as a group or part of a group denotes an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and which may bestraight or branched preferably having 2-14 carbon atoms, morepreferably 2-12 carbon atoms, most preferably 2-6 carbon atoms, in thenormal chain. The group may contain a plurality of double bonds in thenormal chain and the orientation about each is independently E or Z.Exemplary alkenyl groups include, but are not limited to, ethenyl,propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. Thegroup may be a terminal group or a bridging group.

“Alkoxy” refers to an —O-alkyl group in which alkyl is defined herein.Preferably the alkoxy is a C₁-C₆ alkoxy. Examples include, but are notlimited to, methoxy and ethoxy. The group may be a terminal group or abridging group.

“Alkenyloxy” refers to an —O— alkenyl group in which alkenyl is asdefined herein. Preferred alkenyloxy groups are C₁-C₆ alkenyloxy groups.The group may be a terminal group or a bridging group.

“Alkynyloxy” refers to an —O-alkynyl group in which alkynyl is asdefined herein. Preferred alkynyloxy groups are C₁-C₆ alkynyloxy groups.The group may be a terminal group or a bridging group.

“Alkoxycarbonyl” refers to an —C(O)—O-alkyl group in which alkyl is asdefined herein. The alkyl group is preferably a C₁-C₆ alkyl group.Examples include, but not limited to, methoxycarbonyl andethoxycarbonyl. The group may be a terminal group or a bridging group.

“Alkylsulfinyl” means a —S(O)-alkyl group in which alkyl is as definedabove. The alkyl group is preferably a C₁-C₆ alkyl group. Exemplaryalkylsulfinyl groups include, but not limited to, methylsulfinyl andethylsulfinyl. The group may be a terminal group or a bridging group.

“Alkylsulfonyl” refers to a —S(O)₂-alkyl group in which alkyl is asdefined above. The alkyl group is preferably a C₁-C₆ alkyl group.Examples include, but not limited to methylsulfonyl and ethylsulfonyl.The group may be a terminal group or a bridging group.

“Alkynyl” as a group or part of a group means an aliphatic hydrocarbongroup containing a carbon-carbon triple bond and which may be straightor branched preferably having from 2-14 carbon atoms, more preferably2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.Exemplary structures include, but are not limited to, ethynyl andpropynyl. The group may be a terminal group or a bridging group.

“Alkylaminocarbonyl” refers to an alkylamino-carbonyl group in whichalkylamino is as defined above. The group may be a terminal group or abridging group.

“Cycloalkyl” refers to a saturated or partially saturated, monocyclic orfused or spiro polycyclic, carbocycle preferably containing from 3 to 9carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like, unless otherwise specified. It includesmonocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systemssuch as decalin, and polycyclic systems such as adamantane. The groupmay be a terminal group or a bridging group.

“Cycloalkenyl” means a non-aromatic monocyclic or multicyclic ringsystem containing at least one carbon-carbon double bond and preferablyhaving from 5-10 carbon atoms per ring. Exemplary monocycliccycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.The cycloalkenyl group may be substituted by one or more substituentgroups. The group may be a terminal group or a bridging group.

The above discussion of alkyl and cycloalkyl substituents also appliesto the alkyl portions of other substituents, such as without limitation,alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl,alkylsulfonyl and alkyl ester substituents and the like.

“Cycloalkylalkyl” means a cycloalkyl-alkyl- group in which thecycloalkyl and alkyl moieties are as previously described. Exemplarymonocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl and cycloheptylmethyl. The group may be a terminalgroup or a bridging group.

“Halogen” represents fluorine, chlorine, bromine or iodine.

“Heterocycloalkyl” refers to a saturated or partially saturatedmonocyclic, bicyclic, or polycyclic ring containing at least oneheteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10membered, more preferably 4 to 7 membered. Examples of suitableheterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl,tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl,morpholino, 1,3-diazepane, 1,4-diazepane, 1,4-oxazepane, and1,4-oxathiapane. The group may be a terminal group or a bridging group.

“Heterocycloalkenyl” refers to a heterocycloalkyl as described above butcontaining at least one double bond. The group may be a terminal groupor a bridging group.

“Heterocycloalkylalkyl” refers to a heterocycloalkyl-alkyl group inwhich the heterocycloalkyl and alkyl moieties are as previouslydescribed. Exemplary heterocycloalkylalkyl groups include(2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl. The groupmay be a terminal group or a bridging group.

“Heteroalkyl” refers to a straight- or branched-chain alkyl grouppreferably having from 2 to 14 carbons, more preferably 2 to 10 carbonsin the chain, one or more of which has been replaced by a heteroatomselected from S, O, P and N. Exemplary heteroalkyls include alkylethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, andthe like. The group may be a terminal group or a bridging group. As usedherein reference to the normal chain when used in the context of abridging group refers to the direct chain of atoms linking the twoterminal positions of the bridging group.

“Aryl” as a group or part of a group denotes (i) an optionallysubstituted monocyclic, or fused polycyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) preferably having from5 to 12 atoms per ring. Examples of aryl groups include phenyl,naphthyl, and the like; (ii) an optionally substituted partiallysaturated bicyclic aromatic carbocyclic moiety in which a phenyl and aC₅₋₇cycloalkyl or C₅₋₇ cycloalkenyl group are fused together to form acyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. Thegroup may be a terminal group or a bridging group.

“Arylalkenyl” means an aryl-alkenyl- group in which the aryl and alkenylare as previously described. Exemplary arylalkenyl groups includephenylallyl. The group may be a terminal group or a bridging group.

“Arylalkyl” means an aryl-alkyl- group in which the aryl and alkylmoieties are as previously described. Preferred arylalkyl groups containa C₁₋₅ alkyl moiety. Exemplary arylalkyl groups include benzyl,phenethyl and naphthalenemethyl. The group may be a terminal group or abridging group.

“Heteroaryl” either alone or part of a group refers to groups containingan aromatic ring (preferably a 5 or 6 membered aromatic ring) having oneor more heteroatoms as ring atoms in the aromatic ring with theremainder of the ring atoms being carbon atoms. Suitable heteroatomsinclude nitrogen, oxygen and sulphur. Examples of heteroaryl includethiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan,isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole,1H-indazole, purine, quinoline, isoquinoline, phthalazine,naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine,acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole,isoxazole, furazane, phenoxazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-,or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl 1-, 2-, or 3-indolyl, and2-, or 3-thienyl. The group may be a terminal group or a bridging group.

“Heteroarylalkyl” means a heteroaryl-alkyl group in which the heteroaryland alkyl moieties are as previously described. Preferredheteroarylalkyl groups contain a lower alkyl moiety. Exemplaryheteroarylalkyl groups include pyridylmethyl. The group may be aterminal group or a bridging group.

“Lower alkyl” as a group means unless otherwise specified, an aliphatichydrocarbon group which may be straight or branched having 1 to 6 carbonatoms in the chain, more preferably 1 to 4 carbons such as methyl,ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl ortertiary-butyl). The group may be a terminal group or a bridging group.

The compounds may be prepared by any suitable method known to one ofordinary skill in the art. For instance, suitable methods of preparationof the compounds of formulae 1 to 20 above are disclosed in WO2008/003141 (formulae 1 to 7), WO 2009/079692 (formulae 8 to 10), WO2010/144959 (formulae 11 to 16), and WO 2011/047432 (formulae 17 to 20).

It is understood that included in the family of compounds of Formulae 1to 20 are isomeric forms including diastereoisomers, enantiomers,tautomers, and geometrical isomers in “E” or “Z” configurational isomeror a mixture of E and Z isomers. It is also understood that someisomeric forms such as diastereomers, enantiomers, and geometricalisomers can be separated by physical and/or chemical methods and bythose skilled in the art.

Some of the compounds as used in the disclosed embodiments may exist assingle stereoisomers, racemates, and/or mixtures of enantiomers and/ordiastereomers. All such single stereoisomers, racemates and mixturesthereof, are intended to be within the scope of the subject matterdescribed and claimed.

Some of the compounds as used in the disclosed embodiments aresubstituted cyclopropanes having the general formula

The structure shown is intended to include isomeric forms of thecyclopropanes including diastereoisomers and enantiomers.

Additionally, Formulae 1 to 20 are intended to cover, where applicable,solvated as well as unsolvated forms of the compounds. Thus, eachformula includes compounds having the indicated structure, including thehydrated as well as the non-hydrated forms.

In addition to compounds of Formulae 1 to 20, the compounds of thevarious embodiments include pharmaceutically acceptable salts, prodrugs,N-oxides and active metabolites of such compounds, and pharmaceuticallyacceptable salts of such metabolites.

The term “pharmaceutically acceptable salts” refers to salts that retainthe desired biological activity of the above-identified compounds, andinclude pharmaceutically acceptable acid addition salts and baseaddition salts. Suitable pharmaceutically acceptable acid addition saltsof compounds of Formulae 1 to 20 may be prepared from an inorganic acidor from an organic acid. Examples of such inorganic acids arehydrochloric, sulfuric, and phosphoric acid. Appropriate organic acidsmay be selected from aliphatic, cycloaliphatic, aromatic, heterocycliccarboxylic and sulfonic classes of organic acids, examples of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic.Suitable pharmaceutically acceptable base addition salts of compounds ofFormulae 1 to 20 include metallic salts made from lithium, sodium,potassium, magnesium, calcium, aluminium, and zinc, and organic saltsmade from organic bases such as choline, diethanolamine, morpholine.Other examples of organic salts are: ammonium salts, quaternary saltssuch as tetramethylammonium salt; amino acid addition salts such assalts with glycine and arginine. Additional information onpharmaceutically acceptable salts can be found in Remington'sPharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, Pa.1995. In the case of agents that are solids, it is understood by thoseskilled in the art that the inventive compounds, agents and salts mayexist in different crystalline or polymorphic forms, all of which areintended to be within the scope of the present invention and specifiedformulae.

“Prodrug” means a compound which is convertible in vivo by metabolicmeans (e.g. by hydrolysis, reduction or oxidation) to a compound ofFormulae 1 to 20. For example an ester prodrug of a compound of Formulae1 to 20 containing a hydroxyl group may be convertible by hydrolysis invivo to the parent molecule. Suitable esters of compounds of Formulae 1to 20 containing a hydroxyl group, are for example acetates, citrates,lactates, tartrates, malonates, oxalates, salicylates, propionates,succinates, fumarates, maleates, methylene-bis-p-hydroxynaphthoates,gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates,ethanesulphonates, benzenesulphonates, p-toluenesulphonates,cyclohexylsulphamates and quinates. As another example an ester prodrugof a compound of Formulae 1 to 20 containing a carboxy group may beconvertible by hydrolysis in vivo to the parent molecule. (Examples ofester prodrugs are those described by F. J. Leinweber, Drug Metab. Res.,18:379, 1987).

The terms “treating”, “treat”, or “treatment” refer generally toamelioration or elimination of a named condition once the condition hasbeen established. The term “prophylaxis” refers generally to treatmentto prevent the onset of a named condition or of a process that can leadto the condition (“primary” prophylaxis), or the recurrence of symptomsof a condition.

The term “subject” refers generally to any warm blooded animal such as,but not limited to, a mouse, guinea pig, dog, horse, or human. In anembodiment, the subject is human.

The term “therapeutically effective amount” or “effective amount” is anamount sufficient to effect beneficial or desired clinical results. Aneffective amount can be administered in one or more administrations. Aneffective amount is typically sufficient to palliate, ameliorate,stabilize, reverse, slow or delay the progression of the disease state.

The term “pharmaceutically acceptable” refers generally to a substanceor composition that is compatible chemically and/or toxicologically withthe other ingredients including a formulation, and/or the subject beingtreated.

The compounds as utilised in the above five aspects of the presentinvention refers generally to compounds, prodrugs thereof,pharmaceutically acceptable salts of the compounds and/or prodrugs, andhydrates or solvates of the compounds, salts, and/or prodrugs, as wellas all stereoisomers (including diastereoisomers and enantiomers),tautomers and isotopically labelled compounds. The compounds of thepresent invention may exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike, and it is intended that the invention embrace both solvated andunsolvated forms.

The term “derivative thereof” when used in reference to compounds of thepresent invention refers generally to prodrugs, pharmaceuticallyacceptable salts of the compounds and/or prodrugs, and hydrates orsolvates of the compounds, salts, and/or prodrugs.

Administration of compounds of Formulae 1 to 20 or any composition(s)comprising same to subjects can be by any of the accepted modes forenteral administration such as oral or rectal, or by parenteraladministration such as subcutaneous, intramuscular, intravenous andintradermal routes. Injection can be bolus or via constant orintermittent infusion. The active compound is typically included in apharmaceutically acceptable carrier, excipient and/or diluent and in anamount sufficient to deliver to the patient a therapeutically effectivedose.

In using the compounds they can be administered in any form or modewhich makes the compound bioavailable. One skilled in the art ofpreparing formulations can readily select the proper form and mode ofadministration depending upon the particular characteristics of thecompound selected, the condition to be treated, the stage of thecondition to be treated and other relevant circumstances. See RemingtonsPharmaceutical Sciences, 19^(th) edition, Mack Publishing Co. (1995) forfurther information.

The compounds can be administered alone or in the form of apharmaceutical composition in combination with a pharmaceuticallyacceptable carrier, diluent, adjuvant and/or excipient. The compoundsmay be administered as the compounds themselves or in the form of theirpharmaceutically acceptable salts or derivatives.

The compounds are, however, typically used in the form of pharmaceuticalcompositions which are formulated depending on the desired mode ofadministration. Suitable compositions for use in accordance with themethods of the present invention may be prepared according to methodsand procedures that are known to those of ordinary skill in the art andaccordingly may include a pharmaceutically acceptable carrier,excipient, diluent and/or adjuvant. As such in a further embodiment thepresent invention provides a pharmaceutical composition including acompound of Formulae 1 to 20 and a pharmaceutically acceptable carrier,diluent, adjuvant or excipient.

The invention in other embodiments provides a pharmaceutical pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention. In sucha pack or kit can be found a container having a unit dosage of theagent(s). The kits can include a composition comprising an effectiveagent either as concentrates (including lyophilized compositions), whichcan be diluted further prior to use or they can be provided at theconcentration of use, where the vials may include one or more dosages.Conveniently, in the kits, single dosages can be provided in sterilevials so that the physician can employ the vials directly, where thevials will have the desired amount and concentration of agent(s).Associated with such container(s) can be various written materials suchas instructions for use, or a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration.

The compounds may be used or administered in combination with one ormore additional drug(s) for the treatment of the disorder/diseasesmentioned. The components can be administered in the same formulation orin separate formulations or compositions. If administered in separateformulations or compositions, the compounds of the invention or theformulations or compositions comprising same may be administeredsequentially or simultaneously with the other drug(s).

In addition to being able to be administered in combination with one ormore additional drugs, the compounds may be used in a combinationtherapy. When this is done the compounds are typically administered incombination with each other. Thus one or more of the compounds of theinvention may be administered either simultaneously (as a combinedpreparation) or sequentially in order to achieve a desired effect. Thisis especially desirable where the therapeutic profile of each compoundis different such that the combined effect of the two drugs provides animproved therapeutic result. Administration may be systemic, regional orlocal.

Pharmaceutical compositions of the invention may be administered bystandard routes. In general, the compositions may be administered by theparenteral (e.g., intravenous, intraspinal, subcutaneous orintramuscular), oral or topical route. The particular route ofadministration to be used in any given circumstance will depend on anumber of factors, including the nature of the condition to be treated,the severity and extent of the condition, the required dosage of theparticular compound to be delivered and the potential side-effects ofthe compound.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

Examples of pharmaceutically acceptable carriers or diluents aredemineralised or distilled water; saline solution; vegetable based oilssuch as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil,sesame oil, arachis oil or coconut oil; silicone oils, includingpolysiloxanes, such as methyl polysiloxane, phenyl polysiloxane andmethylphenyl polysolpoxane; volatile silicones; mineral oils such asliquid paraffin, soft paraffin or squalane; cellulose derivatives suchas methyl cellulose, ethyl cellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose or hydroxypropylmethylcellulose; lower alkanols,for example ethanol or iso-propanol; lower aralkanols; lowerpolyalkylene glycols or lower alkylene glycols, for example polyethyleneglycol, polypropylene glycol, ethylene glycol, propylene glycol,1,3-butylene glycol or glycerin; fatty acid esters such as isopropylpalmitate, isopropyl myristate or ethyl oleate; polyvinylpyrridone;agar; carrageenan; gum tragacanth or gum acacia, and petroleum jelly.Typically, the carrier or carriers will form from 10% to 99.9% by weightof the compositions.

These compositions may also contain one or more adjuvants such aspreservatives, wetting agents, emulsifying agents, and dispersingagents. Prevention of the action of micro-organisms may be ensured bythe inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents such as sugars, sodiumchloride, and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the inclusion of agents thatdelay absorption such as aluminium monostearate and gelatin.

The compositions of the invention may be in a form suitable foradministration by injection, in the form of a formulation suitable fororal ingestion (such as capsules, tablets, caplets, elixirs, forexample), in the form of an ointment, cream or lotion suitable fortopical administration, in a form suitable for delivery as an eye drop,in an aerosol form suitable for administration by inhalation, such as byintranasal inhalation or oral inhalation, in a form suitable forparenteral administration, that is, subcutaneous, intramuscular orintravenous injection.

For administration as an injectable solution or suspension, non-toxicparenterally acceptable diluents or carriers can include, Ringer'ssolution, isotonic saline, phosphate buffered saline, ethanol and 1,2propylene glycol. The injectable solution or suspension can besterilised, for example, by filtration through a bacterial-retainingfilter, or by incorporating sterilising agents in the form of sterilesolid compositions that can be dissolved or dispersed in sterile wateror other sterile injectable medium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, dextrose,sucrose, glucose, sorbitol, mannitol, and silicic acid, b) binders asacceptable in human and veterinary pharmaceutical practice such as, forexample, carboxymethylcellulose, alginates (e.g. sodium alginate),gelatin, polyvinylpyrrolidone, corn starch, sucrose, and acacia, c)humectants such as glycerol, d) disintegrating agents such as agar,agar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, sodium carbonate, corn starch, methylcellulose,polyvinylpyrrolidone, guar gum, xanthan gum and bentonite, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and/or i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,stearic acid, sodium oleate, sodium chloride and mixtures thereof. Inthe case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in microencapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, sunflower, safflower, arachis, coconut and sesameoils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols,triglycerides, fatty acid esters of sorbitan, lactose, sorbitol,mannitol, dextrose, kaolin, cellulose, calcium carbonate, calciumsilicate and/or dicalcium phosphate and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, osmotic agents, comfort enhancing agents,emulsifying and suspending agents, sweeteners, thickening agents,preservatives, bactericides and/or bacteristatics, buffering agents,time delay agents, flavouring and perfuming agents. Suitable sweetenersinclude sucrose, lactose, glucose, aspartame or saccharine. Suitableflavouring agents include peppermint oil, oil of wintergreen, cherry,orange or raspberry flavouring. Suitable time delay agents includeglyceryl monostearate or glyceryl distearate. Suitable wetting agentscould be selected from the group comprising cellulose derivatives suchas hydroxypropyl methyl cellulose, carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, dextran, gelatin, polyols, liquidsuch as glycerin, polyethylene glycol, polyethylene glycol, polysorbate,propylene glycol, polyvinyl alcohol, povidone (polyvinyl pyrrolidone)and copolymers such as EO/PO block copolymers. Suitable bactericidesand/or bacteristatics include cationic antibacterial agents that bindwith high affinity to negatively charged cell membranes of bacteria bydisplacing divalent cations in the membranes and causing the loss ofessential cellular components (Gilbert and Moore 2005). Accordingly,cationic substances such as biguanides (i.e. salts of alexidine,alexidine free base, salt of chlorhexidine, hexamethylene biguanides,and polymeric biguanides such as polyhexamethylene biguanide [PHMB]),quaternary ammonium compounds (i.e. polyquaternium-1 [POLYQUAD],chemical registry number 75345-27-6; and cetylpyridinium chloride[CPC]), and myristamidopropyl dimethylamine [ALDOX]), povidone-iodine,hydrogen peroxide, benzyl alcohol, indolicidins, ethoxylated alkylglucoside, and non-amine polyethyleneoxide are contemplated herein asnon-limiting examples of cationic antibacterials. Similarly,dimethyldiallylammonium chloride homopolymer and strongly basic anionicexchange ammonium resins are also contemplated herein as non-limitingexamples of antimicrobial agents.

For topical applications in the eye, ionic dissociating compounds assurfactants are contemplated such as lauroylethylenediaminetriacetate,polyethylene glycol fatty acid ester, an alkanolamide, an amide oxide,an ethoxylated alcohol and ethoxylated acid.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof. Suspensions may also include dispersing agents such aslecithin, polyoxyethylene esters of fatty acids such as stearic acid,polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate,polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate andthe like.

The topical compositions of the present invention, comprise an activeingredient together with one or more acceptable carriers, and optionallyany other therapeutic ingredients. Compositions suitable for topicaladministration include liquid or semi-liquid preparations suitable forpenetration through the skin to the site of where treatment is required,such as liniments, lotions, creams, powders, patches, sprays, inhalers,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient is mixed under sterile conditionswith a pharmaceutically acceptable carrier and any needed preservatives,buffers, or propellants which may be required.

Drops according to the present invention may comprise sterile aqueous oroily solutions or suspensions. These may be prepared by dissolving theactive ingredient in an aqueous solution of a bactericidal and/orfungicidal agent and/or any other suitable preservative, and optionallyincluding a surface active agent. The resulting solution may then beclarified by filtration, transferred to a suitable container andsterilised. Sterilisation may be achieved by: autoclaving or maintainingat 90° C.-100° C. for half an hour, or by filtration, followed bytransfer to a container by an aseptic technique. Examples ofbactericidal and fungicidal agents suitable for inclusion in the dropsare phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for thepreparation of an oily solution include glycerol, diluted alcohol andpropylene glycol.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those described above in relation to thepreparation of drops. Lotions or liniments for application to the skinmay also include an agent to hasten drying and to cool the skin, such asan alcohol or acetone, and/or a moisturiser such as glycerol, or oilsuch as castor oil or arachis oil.

Creams, ointments or pastes according to the present invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with a greasy or non-greasy basis. Thebasis may comprise hydrocarbons such as hard, soft or liquid paraffin,glycerol, beeswax, a metallic soap; a mucilage; an oil of natural originsuch as almond, corn, arachis, castor or olive oil; wool fat or itsderivatives, or a fatty acid such as stearic or oleic acid together withan alcohol such as propylene glycol or macrogols.

The composition may incorporate any suitable surfactant such as ananionic, cationic or non-ionic surfactant such as sorbitan esters orpolyoxyethylene derivatives thereof. Suspending agents such as naturalgums, cellulose derivatives or inorganic materials such as silicaceoussilicas, and other ingredients such as lanolin, may also be included.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds withsuitable non-irritating excipients or carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at roomtemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

The amount of compound administered will preferably treat and reduce oralleviate the condition. A therapeutically effective amount can bereadily determined by an attending diagnostician by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount a number of factors are to be considered including but notlimited to, the species of animal, its size, age and general health, thespecific condition involved, the severity of the condition, the responseof the patient to treatment, the particular compound administered, themode of administration, the bioavailability of the preparationadministered, the dose regime selected, the use of other medications andother relevant circumstances.

One skilled in the art would be able, by routine experimentation, todetermine an effective, non-toxic amount of the compound which would berequired to treat applicable diseases and conditions. Generally, atypical and effective dosage is expected to be in the range of about0.01 to about 1000 mg per kilogram of body weight per day, typically ofabout 0.1 to about 100 mg per kilogram of body weight per day, even moretypically of about 1 to about 10 mg per kilogram of body weight per day,and further of about 5 mg per kilogram of body weight per day. Smalldoses (0.01-1 mg/kg per day) may be administered initially, followed byincreasing doses up to about 1000 mg/kg per day. In the event that theresponse in a subject is insufficient at such doses, even higher doses(or effective higher doses by a different, more localised deliveryroute) may be employed to the extent patient tolerance permits. A morepreferred dosage will be in the range from 0.1 to 300 mg per kilogram ofbody weight per day, more preferably from 0.1 to 100 mg per kilogram ofbody weight per day. A suitable dose can be administered in multiplesub-doses per day.

Typically, in therapeutic applications, the treatment would be for theduration of the disease state.

Further, it will be apparent to one of ordinary skill in the art thatthe optimal quantity and spacing of individual dosages such as thenumber of doses of the composition given per day for a defined number ofdays will be determined by the nature and extent of the disease statebeing treated, the form, route and site of administration, and thenature of the particular individual being treated. Also, such optimumconditions can be determined by conventional techniques.

If desired, and for more effective distribution, the compounds can beincorporated into slow release or targeted delivery systems such aspolymer matrices, liposomes, and microspheres.

Liposomes are generally derived from phospholipids or other lipidsubstances, and are formed by mono- or multi-lamellar hydrated liquidcrystals that are dispersed in an aqueous medium. Any non-toxic,physiologically acceptable and metabolisable lipid capable, of formingliposomes can be used. The compositions in liposome form may containstabilisers, preservatives, excipients and the like. The preferredlipids are the phospholipids and the phosphatidyl cholines (lecithins),both natural and synthetic. Methods to form liposomes are known in theart, and in relation to this specific reference is made to: Prescott,Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p. 33 et seq., the contents of which is incorporated herein byreference.

The compositions may be conjugated to an array of polyethylene glycol(PEG) derivatives. The addition of PEG to proteins (PEGylation) is awell established method for decreasing the plasma clearance rates ofproteins, thereby increasing their efficacy (Nucci et al., 1991, Adv.Drug Del. Rev. 6:133). Additional benefits of PEGylation may include,greater stability of proteins, decreased immunogenicity, enhancedsolubility and decreased susceptibility to proteolysis (Sheffield W.2001, Curr Drug Targets Cardiovasc Haematol Disord. 1:1-22). PEGmolecules contain the basic repeating structure of —(OCH₃CH₂)n-OH andare classified into groups according to their molecular weight. PEGderivatives are conjugated to proteins to increase their hydrodynamicradius and in general, their increase in half-life is directly relatedto the size of the PEG chain attached (Sheffield W. 2001, Curr DrugTargets Cardiovasc Haematol Disord. 1:1-22).

The compositions may also be administered in the form of microparticles.Biodegradable microparticles formed from polylactide (PLA),polylactide-co-glycolide (PLGA), and epsilon-caprolactone ({acute over(ε)}-caprolactone) have been extensively used as drug carriers toincrease plasma half life and thereby prolong efficacy (R. Kumar, M.,2000, J Pharm Pharmaceut Sci. 3(2) 234-258). Microparticles have beenformulated for the delivery of a range of drug candidates includingvaccines, antibiotics, and DNA. Moreover, these formulations have beendeveloped for various delivery routes including parenteral subcutaneousinjection, intravenous injection and inhalation.

The compositions may incorporate a controlled release matrix that iscomposed of sucrose acetate isobutyrate (SAIB) and organic solvent ororganic solvents mixture. Polymer additives may be added to the vehicleas a release modifier to further increase the viscosity and slow downthe release rate. SAIB is a well known food additive. It is a veryhydrophobic, fully esterified sucrose derivative, at a nominal ratio ofsix isobutyrate to two acetate groups. As a mixed ester, SAIB does notcrystallize but exists as a clear viscous liquid. Mixing SAIB with apharmaceutically accepted organic solvent such as ethanol or benzylalcohol decreases the viscosity of the mixture sufficiently to allow forinjection. An active pharmaceutical ingredient may be added to the SAIBdelivery vehicle to form SAIB solution or suspension formulations. Whenthe formulation is injected subcutaneously, the solvent diffuses fromthe matrix allowing the SAIB-drug or SAIB-drug-polymer mixtures to setup as an in situ forming depot.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph depicting the number of leukocytes in the retina ofcontrol rats, diabetic rats and diabetic rats treated with FT011 fromthe short term study. Data were expressed mean±SEM. *P<0.05 versuscontrol and #P<0.05 versus diabetes.

FIG. 2 illustrates representative photomicrographs of rhodamine-coupledConcanavalin A stained for endothelium and adherent leukocytes fromretina of control rats (A), diabetic rats (B) and diabetic rats treatedwith FT011 (C).

FIG. 3 is a graph showing changes in retinal ICAM-1 mRNA levels incontrol rats, diabetic rats and diabetic rats treated with FT011. Datawere expressed mean±SEM. *P<0.05 versus control and ^(#)P<0.05 versusdiabetes.

FIG. 4 is a graph illustrating the number of acellular capillaries inPAS stained retinal sections from control rats, diabetic rats anddiabetic rats treated with 100 mg/kg/day FT011 from a long term study.Acellular capillaries were expressed as number of acellular capillariesper field. Data were expressed mean±SEM. *P<0.05 versus control and^(#)P<0.05 versus diabetes.

FIG. 5 illustrates representative photomicrographs of acellularcapillaries from PAS stained retina of control rats (A), diabetic rats(B) and diabetic rats treated with 100 mg/kg/day FT011 (C).

FIG. 6 is a graph depicting the number of leukocytes in the retina ofcontrol rats, diabetic rats and diabetic rats treated with FT061. Datawere expressed mean±SEM. *P<0.05 versus control and #P<0.05 versusuntreated diabetes.

FIG. 7 illustrates representative photomicrographs of rhodamine-coupledConcanavalin A stained for endothelium and adherent leukocytes fromretina of control rats (A), diabetic rats (B) and diabetic rats treatedwith FT061 (C).

FIG. 8 is a graph showing changes in retinal ICAM-1 mRNA levels incontrol rats, diabetic rats and diabetic rats treated with FT061. Datawere expressed mean±SEM. *P<0.05 versus control and ^(#)P<0.05 versusuntreated diabetes.

FIG. 9 is a graph illustrating changes in retinal VEGF mRNA levels incontrol rats, diabetic rats and diabetic rats treated with FT061. Datawere expressed mean±SEM. #P<0.05 versus control.

Embodiments of the invention will now be discussed in more detail withreference to the following examples and figures which are provided forexemplification only and which should not be considered limiting on thescope of the invention in any way.

Examples Animals

The animal studies were conducted with the approval from the AnimalWelfare and Ethics Committee (St Vincent's Hospital and the NationalHealth and Medical Research Foundation of Australia). All rats receivednormal rat chow (Certified Rodent Diet #5002, LabDiet, USA) and drinkingwater ad libitum. All animals were housed in a stable environmentmaintained at 22±1° C. with a 12-hour light/dark cycle commencing at 6am.

Example 1 Test Compound (FT011)

(E)-2-[[3-(3-Methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoicacid (FT011) has the structure:

Diabetic Retinopathy Rats

Ninety, six-week old female, heterozygous (mRen-2)27 rats (St. Vincent'sHospital Animal House, Melbourne, Australia) were assigned to receiveeither 55 mg/kg of streptozotocin (STZ) (Sigma, St. Louis, USA) dilutedin 0.1 M citrate buffer, pH 4.5 or citrate buffer alone (non-diabeticcontrol) by tail vein injection following an overnight fast. In shortterm study, rats were randomly assigned to receive (n=10/group)treatment with either FT011 (100 mg/kg bid gavage) or vehicle for 8weeks. Non-diabetic animals (n=10) served as controls.

In the long term study, at 16 weeks of STZ diabetes rats were randomlyassigned to either treatment (n=15/group) with, FT011 (50 mg/kg/dayBID), FT011 (100 mg/kg BID) or no treatment for a further 16 weeks.Non-diabetic animals (n=15) served as controls. Each week, rats wereweighed and their blood glucose levels were measured (Accu-checkAdvantage II Blood Glucose Monitor, Roche Diagnostics, USA) and onlySTZ-treated animals with blood glucose >15 mmol/L were considereddiabetic. Every 4 weeks, SBP was determined in preheated conscious ratsvia tail-cuff plethysmography using a non-invasive blood pressure (NIBP)controller and Powerlab (AD instruments, NSW, Australia). HaemoglobinA1c (HbA1c) was measured by HPLC at the end of the study in theDepartment of Pathology, St Vincent's Hospital. Diabetic rats received adaily injection of insulin (2-4 units intraperitoneally; Humulin NPH,Eli Lilly and Co., Indianapolis, Ind.) to reduce mortality and topromote weight gain.

Leukostasis (Short Term Study)

At the end of the short term 8 week study, rats were anaesthetized withLethobarb (60 mg/kg) and the chest cavity was opened. Animals wereperfused via the left ventricle with 0.1M phosphate buffered saline(PBS) to remove non-adherent blood cells. The rats were then perfusedwith rhodamine-coupled Concanavalin A (25 mg/kg, Vector Laboratories) tostain endothelium and adherent leukocytes. Eyes were enucleated andfixed with 4% paraformaldehyde in 0.1M PBS for 30 minutes. Retinae weredissected and flat mounted on microscope slides then visualised on anepi-fluorescent microscope. The total number of leukocytes was countedper retina. The investigator was masked to the group.

Real Time PCR (Short Term Study)

At the end of the short term 8 week study, rats were anaesthetized withlethobarb (60 mg/kg), eyes were enucleated and retinae dissected andplaced in RNAlater (#R0901, Sigma-Aldrich). Total RNA was extracted withan RNeasy Mini Kit (#74104, Qiagen) according to manufacturers'instructions. RNA concentration was determined on a Nanodrop 3.1.2,after which 1 μg of RNA was DNase treated (DNA-free kit, Ambion) andreverse transcribed (First Strand cDNA Synthesis Kit for RT-PCR, Roche).Primers, probes (See Table) and cDNA were mixed with Taqman UniversalMaster Mix (#4304437, Applied Biosystems) and real-time PCR wasconducted using an ABI 7900 HT Sequence Detection System (AppliedBiosystems). mRNA was normalised to 18S rRNA endogenous control and therelative fold difference in expression calculated using the 2-^(ΔΔ)CTmethod.

Primer and Probe for ICAM-1

Accession Primers and Taqman  Gene Species number probe (MGB, FAM label)ICAM1 rat NM_012967 Forward Primer: AGTGCTGTACCATGAT CAGAATACCT Probe: TGA TCATTGCGGGCT Reverse Primer: TAAATGGACGCCACGA TCAC 18S eukaryoteX03205.1 Applied Biosystems  gene expression assay -endogenous control -  VIC label

Trypsin Digest (Long Term Study 32 Weeks)

At the end of long term 32 week study, rats were anaesthetised withLethobarb (60 mg/kg), and then eyes were enucleated and fixed in 2%Carsons Fixative overnight. Retinae were dissected and washed in 0.2MTris Buffer (pH 8.0) followed by digestion in 1% Trypsin (#T4799,Sigma-Aldrich) in 0.2M Tris buffer at 37° C. for one hour. Retinae werethen incubated in 1% Triton X in 0.2M Tris buffer for approximately onehour. Subsequently, retinae were flat mounted on a microscope slide anddried overnight. Slides were stained with Periodic Acid Schiff's Stainto observe acellular capillaries.

Quantification was performed by scanning the entire retina with a 10×objective on a Zeiss Observer microscope system. Random 600 μm×800 μmfields were placed over the entire retina using Adobe Photoshop CS2.Acellular capillaries were counted per field with 10 retinae per groupquantitated. Investigators were masked to the group. Data was analysedas an average of acellular capillaries per field.

Statistics

Statistics were performed using the Shapiro Wilkinson test fornormality. A Krukal-Wallis test followed by Mann Whitney U test wasperformed for statistical significance of nonparametric data.

Results

TABLE 1 Animal characteristics (8 weeks study) Group Body Weight (g) SBP(mmHg) HbA1C (%) Control 289 ± 4 179 ± 8  3.7 ± 0.06 Diabetes 274 ± 6217 ± 10*  11 ± 0.19** Diabetic + FT011  278 ± 12 190 ± 14  8.9 ±0.50^(#) (200 mg/kg/day) *P < 0.05 and **P < 0.01 versus control; ^(#)P< 0.05 versus untreated diabetes

TABLE 2 Animal characteristics (32 weeks study) Group Body Weight (g)SBP (mmHg) HbA1C (%) Control  353 ± 11 152 ± 7  5.4 ± 0.5 Diabetes 324 ±7 160 ± 8  8.4 ± 0.29* Diabetic + FT011 322 ± 8  176 ± 10 7.65 ± 0.25*(100 mk/kg/day) Diabetic + FT011 313 ± 9 170 ± 7 6.58 ± 0.37^(#) (200mk/kg/day) *P < 0.05 versus control; ^(#)P < 0.05 versus untreateddiabetes

FIG. 1 demonstrates the total number of leukocytes in the retina fromthe short term study were significantly less in diabetic rats treatedwith FT011 compared to untreated diabetic rats.

The representative micrographs in FIG. 2 show that in diabetic rats (B)numerous leukocytes were observed in the capillaries (designated witharrows) when compared to control (A), and treatment with FT011significantly reduced leukostasis (C).

FIG. 3 shows there was an increase in ICAM-1 mRNA levels in diabeticrats when compared to controls. Moreover, treatment with FT011 wasassociated with a reduction in ICAM-1 mRNA levels.

In FIG. 4 a quantitative assessment of acellular capillaries was made bycounting the number of capillaries in PAS stained retinal sections fromthe long term study. Clearly, there were less acellular capillaries indiabetic rats treated with FT011 compared to untreated diabetic rats.

The representative micrographs in FIG. 5 show that In diabetic rats (B)acellular capillaries (pericyte ghost) were observed (arrow), whilepericyte ghosts were not apparent in control (A) and diabetic ratstreated with FT011 (C).

Example 2 Test Compound (FT061)

(E)-2-[[3,4-Bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoicacid (FT061) has the structure:

Diabetic Retinopathy Rats

Sixty, six-week old female, heterozygous (mRen-2)27 rats (St. Vincent'sHospital Animal House, Melbourne, Australia) were assigned to receiveeither 55 mg/kg of streptozotocin (STZ) (Sigma, St. Louis, USA) dilutedin 0.1 M citrate buffer, pH 4.5 or citrate buffer alone (non-diabeticcontrol) by tail vein injection following an overnight fast. Rats wererandomly assigned to receive (n=15/group) treatment with either FT061(100 mg/kg/day gavage) or vehicle for 8 weeks. Non-diabetic animals(n=15) served as controls. Each week, rats were weighed and their bloodglucose levels were measured (Accu-check Advantage II Blood GlucoseMonitor, Roche Diagnostics, USA) and only STZ-treated animals with bloodglucose >15 mmol/L were considered diabetic. Every 4 weeks, SBP wasdetermined in preheated conscious rats via tail-cuff plethysmographyusing a non-invasive blood pressure (NIBP) controller and Powerlab (ADinstruments, NSW, Australia). Diabetic rats received a daily injectionof insulin (2-4 units intraperitoneally; Humulin NPH, Eli Lilly and Co.,Indianapolis, Ind.) to reduce mortality and to promote weight gain.

Leukostasis

At the end of the study, rats were anaesthetized with Lethobarb (60mg/kg) and the chest cavity was opened. Animals were perfused via theleft ventricle with 0.1M phosphate buffered saline (PBS) to removenon-adherent blood cells. The rats were then perfused withrhodamine-coupled Concanavalin A (25 mg/kg, Vector Laboratories) tostain endothelium and adherent leukocytes. Eyes were enucleated andfixed with 4% paraformaldehyde in 0.1M PBS for 30 minutes. Retinae weredissected and flat mounted on microscope slides then visualised on anepi-fluorescent microscope. The total number of leukocytes was countedper retina. The investigator was masked to the group.

Real Time PCR

At the end of the study, rats were anaesthetized with lethobarb (60mg/kg), eyes were enucleated and retinae dissected and placed inRNAlater (#R0901, Sigma-Aldrich). Total RNA was extracted with an RNeasyMini Kit (#74104, Qiagen) according to manufacturers' instructions. RNAconcentration was determined on a Nanodrop 3.1.2, after which 1 g of RNAwas DNase treated (DNA-free kit, Ambion) and reverse transcribed (FirstStrand cDNA Synthesis Kit for RT-PCR, Roche). Primers, probes (SeeTable) and cDNA were mixed with Taqman Universal Master Mix (#4304437,Applied Biosystems) and real-time PCR was conducted using an ABI 7900 HTSequence Detection System (Applied Biosystems). mRNA was normalised to18S rRNA endogenous control and the relative fold difference inexpression calculated using the 2-^(ΔΔ)CT method.

Primer and Probe for ICAM-1 and VEGF

Primers and Accession Taqman probe  Gene Species number (MGB, FAM label)ICAM1 rat NM_012967 Forward Primer: AGTGCTGTACCATGAT CAGAATACCT Probe: TGA TCATTGCGGGCT Reverse Primer TAAATGGACGCCACGA TCAC VEGF ratNM_031836.2 Applied Biosystems  NM_001110333.1 gene expressionNM_001110334.1 assay - FAM label 18S eukaryote X03205.1Applied Biosystems  gene expression assay - endogenous control - VIC label

Statistics

Statistics were performed using the Shapiro Wilkinson test fornormality. A Krukal-Wallis test followed by Mann Whitney U test wasperformed for statistical significance of nonparametric data.

Results

TABLE 1 Animal characteristics Group Body Weight (g) SBP (mmHg) Control308 ± 8  192 ± 6 Diabetes 292 ± 10  201 ± 10 Diabetic + FT061 282 ± 4#178 ± 4 #P < 0.05 versus control

FIG. 6 demonstrates the total number of leukocytes in the retina wassignificantly less in diabetic rats treated with FT061 compared tountreated diabetic rats.

The representative photomicrographs in FIG. 7 show that in diabetic rats(B) numerous leukocytes were observed in the capillaries (designatedwith arrows) when compared to control (A), and treatment with FT061significantly reduced leukostasis (C).

FIG. 8 illustrates a quantitative real time PCR assessment of retinalICAM-1 mRNA levels. FIG. 8 shows there was an increase in ICAM-1 mRNAlevels in diabetic rats compared to controls. Moreover, treatment withFT061 was associated with a reduction in ICAM-1 mRNA levels whencompared to controls and untreated diabetes.

In FIG. 9 a quantitative real time PCR assessment of retinal VEGF mRNAlevels showed treatment with FT061 was associated with a reduction inVEGF mRNA levels when compared to controls and untreated diabetes.

It will of course be realised that the above has been given only by wayof illustrative example of the invention and that all such modificationsand variations thereto as would be apparent to persons skilled in theart are deemed to fall within the broad scope and ambit of the inventionas herein set forth.

REFERENCES

-   Adamis, A. P. (2002). “Is diabetic retinopathy an inflammatory    disease?” Br J Ophthalmol 86(4): 363-5.-   Aiello, L. M. (2003). “Perspectives on diabetic retinopathy.” Am J    Ophthalmol 136(1): 122-35.-   Arita, R., Y. Hata, et al. “ROCK as a Therapeutic Target of Diabetic    Retinopathy.” J Ophthalmol 2010: 175163.-   Cheung, A. K., M. K. Fung, et al. (2005). “Aldose reductase    deficiency prevents diabetes-induced blood-retinal barrier    breakdown, apoptosis, and glial reactivation in the retina of db/db    mice.” Diabetes 54(11): 3119-25.-   Joussen, A. M., V. Poulaki, et al. (2004). “A central role for    inflammation in the pathogenesis of diabetic retinopathy.” Faseb J    18(12): 1450-2.-   Joussen, A. M., V. Poulaki, et al. (2002). “Nonsteroidal    anti-inflammatory drugs prevent early diabetic retinopathy via    TNF-alpha suppression.” Faseb J. 16(3): 438-40.-   Joussen, A. M., V. Poulaki, et al. (2002). “Retinal vascular    endothelial growth factor induces intercellular adhesion molecule-1    and endothelial nitric oxide synthase expression and initiates early    diabetic retinal leukocyte adhesion in vivo.” Am J Pathol 160(2):    501-9.-   Khalfaoui, T., G. Lizard, et al. (2009). “Immunohistochemical    analysis of cellular adhesion molecules (ICAM-1, VCAM-1) and VEGF in    fibrovascular membranes of patients with proliferative diabetic    retinopathy: preliminary study.” Pathol Biol (Paris) 57(7-8): 513-7.-   Klein, R., B. E. Klein, et al. (2004). “The relation of retinal    vessel caliber to the incidence and progression of diabetic    retinopathy: XIX: the Wisconsin Epidemiologic Study of Diabetic    Retinopathy.” Arch Ophthalmol 122(1): 76-83.-   Santos, K. G., B. Tschiedel, et al. (2005). “Prevalence of    retinopathy in Caucasian type 2 diabetic patients from the South of    Brazil and relationship with clinical and metabolic factors.” Braz J    Med Biol Res 38(2): 221-5.-   Sarlos, S., B. Rizkalla, et al. (2003). “Retinal angiogenesis is    mediated by an interaction between the angiotensin type 2 receptor,    VEGF, and angiopoietin.” Am J Pathol 163(3): 879-87.-   Watkins, P. J. (2003). “Retinopathy.” Bmj 326(7395): 924-6.-   Zammit, S. C., A. J. Cox, et al. (2009). “Evaluation and    optimization of antifibrotic activity of cinnamoyl anthranilates.”    Bioorg Med Chem Lett 19(24): 7003-6.

1-41. (canceled)
 42. A method for treating an eye disease associatedwith inflammation and/or vascular proliferation in a subject comprisingadministering to the subject a therapeutically effective amount of acompound of the formula

or a pharmaceutically acceptable salt thereof; wherein the eye diseaseis selected from the group consisting of corneal edema, anterior andposterior uveitis, pterygium, corneal diseases, dry eye, conjunctivitis,allergy- and laser-induced exudation, non-age related maculardegeneration, macular edema, age-related macular degeneration, andocular von Hippel-Lindau disease.
 43. The method of claim 42, whereinthe eye disease is age-related macular degeneration.
 44. The method ofclaim 42, wherein the eye disease is non-age related maculardegeneration.
 45. The method of claim 42, wherein the eye disease ismacular edema.
 46. The method of claim 42, wherein the eye disease isdry eye.
 47. The method of claim 42, wherein the administration of thecompound to the subject reduces the number of acellular capillaries inthe retina of the subject.
 48. The method of claim 42, wherein theadministration of the compound to the subject reduces the level ofICAM-1 mRNA in the retina of the subject.
 49. The method of claim 42,wherein the administration of the compound to the subject reduces thelevel of VEGF mRNA in the retina of the subject.
 50. The method of claim42, wherein the administration of the compound to the subject reducesthe number of leukocytes in the retina of the subject.
 51. The method ofclaim 42, comprising administering a therapeutically effective amount ofthe compound to the eye of the subject.
 52. The method of claim 42,comprising administering a therapeutically effective amount of thecompound orally to the subject.
 53. The method of claim 42, whereintreating the eye disease includes inhibiting the progression of the eyedisease, preventing the eye disease, and/or ameliorating a symptom ofthe eye disease.
 54. The method of claim 42, wherein the corneal diseaseis caused by infection from a microbe or microorganism.
 55. The methodof claim 54, wherein the microbe or microorganism is bacteria, viruses,fungi, amoeba, or parasites.